Cirrhosis is a consequence of acute and chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis C, toxins and fatty liver but has many other possible causes.
Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy and bleeding from esophageal varices. Today, cirrhosis is generally irreversible once it occurs, and treatment generally focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant.
Modern medicine defines hepatic encephalopathy (HE) as a neuropsychiatric syndrome, which is associated with acute or chronic liver dysfunction and has quantitatively and qualitatively distinct features relating to its severity. In cirrhosis, cerebral dysfunction is heterogeneous ranging from mild neuropsychiatric and psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities and poor concentration to severe features such as confusion, stupor, coma and eventually death.
Hepatic encephalopathy is caused by disorders affecting the liver including disorders that reduce liver function (such as cirrhosis or hepatitis) and conditions where there is impaired blood circulation in the liver.
While the symptoms of hepatic encephalopathy are well documented, its pathogenesis is not clear yet and a number of possible scenarios have been suggested. First, liver failure induces impaired glucose oxidative pathways and increased lactate synthesis in the brain which results in energy failure. Second, hypoglycemia and hypoxia are also major contributors to the energy failure seen in hepatic encephalopathy. Third, ammonia is considered to play a major role in the pathogenesis of the neuropsychiatric disturbances observed in hepatic encephalopathy. The liver is the major organ for detoxifying ammonia. When the liver fails the body is incapable of efficiently converting ammonia to urea or glutamine, resulting in systemic hyperammonemia including the brain. Unlike the liver, the brain lacks an effective urea cycle and therefore relies entirely on glutamine synthesis for the removal of blood-borne ammonia. Since glutamine synthetase is dependent on an adequate level of ATP to amidate glutamate to glutamine, ammonia intoxication results in depletion of brain ATP resources and eventually cell death (Ott et al., 2005; Hardie, 2004). Finally, decreased glucose utilization in the brain may be compensated by mobilization of amino acids to provide carbon skeletons as substrates for energy metabolism. Yet, attempts to balance energy failure at the expense of cerebral proteins may end in destructive brain proteolysis (Hardie and Carling, 1997).
However, other factors such as an inflammatory response and astrogliosis in the brain are also implicated in hepatic encephalopathy.
The AMP-activated protein kinase (AMPK) is an evolutionarily conserved metabolic master switch. AMPK is allosterically activated by 5′-AMP, which accumulates following ATP hydrolysis. Conversely, high ATP antagonizes the activating effects of 5′-AMP on AMPK. AMP binding to AMPK leads to activation of the enzyme by inducing a conformational change exposing threonine-172 in the catalytic domain, which undergoes phosphorylation by an upstream AMPK kinase (AMPKK) (Hawley et al., 1996).
Once activated, it switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis) both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression (Foretz et al., 2006). Stresses such as nutrient depletion, hypoxia, heat shock, metabolic poisoning and exercise, all activate AMPK by their effect on the ratio of 5′-AMP to ATP. AMPK, in turn, phosphorylates multiple targets, which switch off anabolic pathways and stimulate catabolic ones. AMPK was recently recognized as a key regulator of whole body energy metabolism (Minokoshi et al., 2004). Cerebral AMPK responds to integration of nutritional and hormonal input. Hypothalamic AMPK controls energy balance via regulation of food intake, body weight and glucose and lipid homeostasis (Dagon et al., 2005; Pagotto et al., 2005). Hippocampal AMPK controls cognitive function via regulation of neurogenesis and neuroapoptosis (Dagon et al, 2005).
The cannabinoid (CB) system consists of two receptor subtypes. The CB-1 receptors are predominantly found in the brain, while the CB-2 receptors are mostly found in the peripheral tissue (Matsuda, et al., 1990). The main endogenous endocannabinoids are small molecules derived from membrane arachidonic acid, such as anandamide(arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG) (Iversen, 2000; Berry et al., 2002). D9-tetrahydrocannabinol (THC), the major psychoactive constituent of the Cannabis plant, is a cannabinoid agonist which produces a myriad of complex pharmacological effects (Baker et al., 2003; Avraham et al., 2006). It is now recognized that most of the central effects of endogenous as well as exogenous cannabinoids are mediated through the CB-1 receptor, a family of G-protein-coupled receptors. Cerebral CB-1 receptors are part of the complex mechanisms involved in the control of energy balance via regulation of food intake and body weight (Teixeira-Clerc et al., 2006). The endocannabinoid system has also been demonstrated to exert neuroprotective effects in several types of cerebral insults via regulation of motor control, cognition, emotional responses, motivated behavior and homeostasis (Julien et al., 2005).
The endocannabinoid system was shown to have an important role in the pathogenesis of hepatic encephalopathy. Modulation of this system, either by specific antagonists to the CB1 cannabinoid receptor, or by agonists specific for the CB2 receptor, such as HU-308 was shown to be effective (Avraham et al., 2006).